tbuckley/cabot-search huggingface dataset:
Abstract 1329: Aging increases malignant peritoneal mesothelioma metastasis
Authors: Mykayla Miller
Journal: Cancer Research (2023)

Abstract Mesothelioma is a rare cancer with approximately 3,000 new cases each year. There are three types of mesotheliomas including pleural (75%), pericardial (&amp;gt;1%) and peritoneal (20%). Mesothelioma occurs in the mesothelial cells, which form a protective barrier to multiple organs. Malignant peritoneal mesothelioma (MPM) is initiated in the peritoneum, a serous membrane that lines the inner walls of the abdominal cavity and the outside of the visceral organs and is a very receptive environment for malignancy and metastasis. MPM metastasizes to the abdominal cavity, affecting the omentum, liver, stomach, intestines, and kidneys. MPM is extremely difficult to diagnose due to its vague symptoms, such as abdominal distension, abdominal pain, weight loss, and nausea. Due to difficulty in diagnosis, most patients are diagnosed at an advanced disease (stage III or IV) with a very poor prognosis with a 9% 5-year survival rate. Asbestos exposure is a major risk factor for MPM with symptoms taking 20-50 years post- exposure to appear, making MPM prominent in aged adults. Mesothelin (MSLN), a 40 kDa protein, is normally expressed on the surface of mesothelial cells and manifests at abnormally high levels in several carcinomas including malignant peritoneal mesothelioma. The exact role of mesothelin is not yet fully understood as mesothelin knockout mice do not display an abnormal phenotype. However, there is some evidence to suggest that mesothelin is involved in tumor cell adhesion by binding to the tumor antigen MUC16. Mesothelin wild-type (WT) and knockout (KO) mice were used to investigate the role of host mesothelin expression on MPM metastasis. A MPM cell line was tagged with nuclear red fluorescence protein (RFP) and injected into the abdomen of female C57Bl/6, young (3-6 months) and aged (18-23 months), MSLN WT or KO mice. Disease progression was evaluated post injection of tumor cells by fluorescent in vivo imaging prior to end point dissection. The abdominal cavity was imaged in situ and tumor burden was evaluated using Image J. Overall, aged mice had increased abdominal tumor burden regardless of host MSLN expression. Aged MSLN KO mice displayed an increase in abdominal tumor burden compared to aged MSLN WT mice, however this difference was not significant. Interestingly, the immune profile of the abdominal cavity of tumor naive mice displays a decrease in natural killer (NK) cells and peritoneal macrophages in aged mice suggesting a role in regulating metastatic peritoneal mesothelioma and could possibly be targets for new immunotherapies. This study demonstrates host age increases tumor growth and metastatic success in peritoneal mesothelioma. Citation Format: Mykayla Miller. Aging increases malignant peritoneal mesothelioma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1329.
A phase Ⅰ/Ⅱa study of cetuximab combined with fruquintinib in the previously treated RAS/BRAF wild-type metastatic colorectal cancer: Results of the CEFRU study.
Authors: Yong Li, Haibo Zhang, Ling Huang, Yi-hong Liu, Xian Chen, Xin Qu, Li-rong Liu, Fangfang Hou, Yongsong Ye
Journal: Journal of Clinical Oncology (2023)

e15558 Background: The standard third-line treatment for mCRC is regorafenib, fruquintinib or TAS-102. However, the efficacy was not satisfied. Since VEGF and EGFR share the downstream signaling pathway, targeting these two pathways may have synergistic efficacy. The phase Ib trial with regorafenib combined with cetuximab have shown preliminary benefit. Fruquintinib is a small molecule highly selective VEGFR1/2/3 molecule inhibitor. Here, we evaluate the safety and efficacy of fruquintinib plus cetuximab in previously treated RAS/BRAF wild-type mCRC. Methods: This is an open-label phase I/IIa study. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3+3 dose escalation strategy in phase I and safety, grade 3/4 adverse events in phase IIa. Secondary objectives include ORR, mPFS, and mOS. Eligible patients were diagnosed as advanced RAS/BRAF wild-type CRC and had received at least two prior regimens of standard therapies. Exclude patients who have previously used other small molecule anti-vascular inhibitors. The planned number of cases is 20(including phaseⅠandⅡa). ChiCTR2000038227. Results: Between Sep, 2020 to Sep, 2022, 21 pts were enrolled including 7 patients of phase Ⅰ. The RP2D is fruquintinib 4 mg QD (3 weeks on/1 week off) plus cetuximab 500mg/m2 every two weeks, received by 17 pts. Two patient dropped out，one because of refusing treatment and another due to severe allergic reaction. 15 pts were included in the efficacy analysis and 16 pts in the safety analysis. The left side mCRC accounted for 87.5%. 68.8% have received cetuximab and 75% have received bevacizumab. The overall TRAE was 75.0%, with 25.0% grade 3 or above. The most common treatment-related AEs were acneiform rash, hypoproteinemia and dry skin (Table1). One patient had dose reduction of fruquintinib due to acneiform rash. Evaluation in 15 treated patients showed 2 cases were PR, 10 were SD and 3 were PD. DCR was 80%. mPFS was 128 days(95%CI:49.7-206.3). mOS was 229 days(95%CI: 104.0-354.0). Conclusions: Cetuximab combined with fruquintinib showed promising anti-tumor activity in CRC with resistance to at least two prior regimens. The toxicity was tolerable and no unexpected toxicities were observed (Table 1). Clinical trial information: Clinical trial information: ChiCTR2000038227 . [Table: see text]
Abstract 6327: Intratumoral administration of ultra high-concentration nitric oxide (UNO) is more efficacious than anti-PD1 therapy in 4T1 tumor-bearing mice
Authors: Yana Epshtein, Matan Goldshtein, Selena Chaisson, Jedidiah Monson, Matt Johnson, Amir Avniel, Steve Lisi, Hila Confino
Journal: Cancer Research (2023)

Abstract Background: For the majority of metastatic triple-negative breast cancer (mTNBC) patients, chemotherapy is the standard first-line treatment, however, outcomes in this population are poor. A monoclonal antibody against the immune checkpoint inhibitor anti-programmed death 1 (PD-1) also has antitumor activity in patients with mTNBC. Previously, we reported that delivering ultra-high concentrations of nitric oxide (UNO) to mouse colon tumors stimulated innate and adaptive immune responses leading to the rejection of secondarily-induced tumors. Moreover, adding an anti-PD-1 antibody to UNO treatment resulted in primary tumor regression in 53% of the mice, the rejection of a distant tumors in all mice, and prolonged survival compared to control and anti-PD-1 arms. In this in vivo study, we investigated the ability of UNO to improve the efficacy of anti-PD-1 antibody treatment in the aggressive mouse breast cancer model, 4T1. Methods: We tested two treatment protocols: 4T1 mice tumors were treated with either a single dose of UNO and anti-PD-1 or a repeated dose of UNO and anti-PD-1. In the single dose design, 4T1 tumors were treated with a single administration of UNO combined with Anti-PD1 administration starting one day after UNO treatment (n=9-10 mice per group). In the repeated dosing design, 4T1 tumors were treated with UNO twice combined with Anti-PD-1 administration starting on the first UNO treatment day (n=8 mice per group). • UNO treatment regimen: 50,000 ppm, 10 minutes, flow rate ~0.2 liters per minute • Anti-PD1 treatment regimen: 10 mg/kg antibody was administered every 3 days for a total of 5 treatments. Results (UNO Single Dose): The primary tumors of 4T1 tumor-bearing mice were 13.2% smaller in the combined single-dose UNO group compared to anti-PD-1 alone 15 days post-UNO treatment. Results (UNO Repeated Dosing): The primary tumors of 4T1 tumor-bearing mice were 25.2% smaller in the combined repeated dose UNO group compared to the anti-PD-1 alone group 16 days after the first UNO treatment. Conclusion: Treating 4T1 tumors with single and repeated doses of UNO improved outcomes compared to anti-PD-1 alone. This suggests that local short-term treatment with UNO can serve as a treatment option for cancer patients with tumors that are not amenable to immune checkpoint inhibitor treatment. Citation Format: Yana Epshtein, Matan Goldshtein, Selena Chaisson, Jedidiah Monson, Matt Johnson, Amir Avniel, Steve Lisi, Hila Confino. Intratumoral administration of ultra high-concentration nitric oxide (UNO) is more efficacious than anti-PD1 therapy in 4T1 tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6327.
Abstract 2909: Genetically engineered Natural Killer cells as an immunotherapeutic approach for the treatment of neuroblastoma
Authors: Tayler J. Croom-Perez, Jeremiah L. Oyer, Md Faqrul Hasan, Liza D. Robles-Carrillo, Brian P. Tullius, Alicja J. Copik
Journal: Cancer Research (2023)

Abstract In this study we test if knockout of DNAM-1 competing inhibitory receptors on Natural Killer (NK) cells improves cytotoxic response against neuroblastoma cell lines. Neuroblastoma and other peripheral nervous cell tumors account for 6% of all pediatric cancer. While the 5-year survival rate has greatly improved, the prognosis of children with high-risk neuroblastoma at diagnosis is less than 50%. Immune checkpoint therapy is a promising new application for pediatric oncology; however, neuroblastoma is often immunologically “cold” and current immune checkpoint targets are not abundant in pediatric solid tumors. To improve response to checkpoint blockade and directly target tumor cells for elimination, this study evaluated the use of NK cells. NK cells prime the immune system for successful response to cancer immunotherapy. NK cells activated with particle technology (PM21-NK cells) are highly cytotoxic, produce IFNγ and induce PD-L1 on cancer cells. Although highly cytotoxic, PM21-NK cells express inhibitory receptors that compete for ligands that trigger NK cell lysis, such as PVR, a ligand highly expressed on neuroblastoma cells. We knocked out expression of multiple PVR inhibitory receptors in PM21-NK cells to further enhance cytotoxicity and prevent exhaustion. Three inhibitory receptors on NK cells that bind PVR - TIGIT, CD96, and PVRIG were knocked out alone or in combination and effector functions of these edited NK cells tested. Cytotoxicity against 3D spheroids of the neuroblastoma cell line SK-NA-S cells was assessed and compared to wild type PM21-NK cells. Knockout (KO) of TIGIT enhanced NK cell killing compared to wildtype NK cells (72%±10 vs 55%±3% killing) as well as PVIRG KO (84±3% vs 46±6% killing) and CD96 KO (62%±9% vs 46±6% killing) at a 1:3 E:T ratio at 72 h. Double or triple KO of these receptors resulted in further increased killing of cancer cells. The knockouts of each of the receptors could affect cytokine production and cytokine responsiveness and this will be examined. Overall, PM21-NK cells show promise for therapeutic use against neuroblastoma and preventing the PVR-mediated inhibitory axis signaling enhances their function. Citation Format: Tayler J. Croom-Perez, Jeremiah L. Oyer, Md Faqrul Hasan, Liza D. Robles-Carrillo, Brian P. Tullius, Alicja J. Copik. Genetically engineered Natural Killer cells as an immunotherapeutic approach for the treatment of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2909.
Abstract 3642: SPHK1 mediated regulation of antitumor immunity in ovarian cancer
Authors: Prachi Gupta, Sudhir Kumar, Ishaque Pulikkal Kadamberi, Sonam Mittal, Jasmine George, Anjali Geethadevi, Pradeep Chaluvally-Raghavan, Sunila Pradeep
Journal: Cancer Research (2023)

Abstract Introduction: Sphingosine kinase 1 (SPHK1) is an enzyme that helps to synthesize biolipid sphingosine-1-phosphate (S1P). We showed extracellular vesicles facilitate an increased accumulation of S1P in the ovarian tumor microenvironment (TME). S1P enhances the exhaustion of CD8 T cells, thus downregulating anti-tumor immunity. Furthermore, we also found less ovarian tumor burden in SPHK1−/− mice compared to WT mice. Based on our preliminary data, we hypothesized that the SPHK1 depleted tumor microenvironment increases the infiltration of the immune cells and its activity downregulates the tumor progression. Methods: SPHK1 global knockout mice and WT C57BL/6 mice were used in the study. Tumor cells (ID8 P53−/− BRCA−/−) were injected, and tumor progression was studied. Immunophenotyping was performed by flow cytometry on ascites and tumor samples. Activation of CD8 T cells, B cells, and dentritic cells were studied by flow cytometry. Bulk RNA sequencing was performed on SPHK1−/− and WT tumors. Results: SPHK1−/− mice showed regression in tumor growth in multiple tumor models. Tumor tissues from SPHK1−/− mice enhanced infiltration of CD4 and CD8 T cells, B cells, and dentritic cells compared to WT mice. Furthermore, infiltrated immune cells were active in SPHK1−/− mice. Bulk RNA sequencing also showed enhanced immune response in SPHK1−/− tumors compared to WT tumors. Conclusion: SPHK1−/- environment decreased the tumor growth by enhancing the infiltration and activation of immune cells. We are currently focusing on identifying the immune cells which are critical players in this process. We will further implement these findings in human immune cells for clinical benefits for ovarian cancer patients. Citation Format: Prachi Gupta, Sudhir Kumar, Ishaque Pulikkal Kadamberi, Sonam Mittal, Jasmine George, Anjali Geethadevi, Pradeep Chaluvally-Raghavan, Sunila Pradeep. SPHK1 mediated regulation of antitumor immunity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3642.
Abstract 6336: Heterodimeric Fc-fused IL12 shows potent antitumor activity and low toxicity
Authors: Yang Huang, Wenting Liu, Dayan Zhang, Pengfei Zhou, Weiming Zhou, Xiaoli Zeng, Qun Zhao, Liangwei Li, Guodong Shen, Liansheng Cheng
Journal: Cancer Research (2023)

Abstract Background: Interleukin-12 (IL12) is a heterodimeric pro-inflammatory cytokine (70 kDa) composed of two different polypeptide chains: an α-chain (p35 subunit) and a β-chain (p40 subunit). IL12 could induce the proliferation and cytotoxicity of T and NK cell and production of interferon-γ (IFN-γ), promote the differentiation of T helper 1 (TH1) cells and regulate innate resistance and adaptive immunity. However, the clinical efficacy of IL12 has been hindered for its high dose-related toxicities and short serum half-life. Here we have developed a heterodimeric Fc-fused IL12, HK054-V, with reduced potency to improve tolerability and prolong half-life. Methods: We assessed the binding, bioactivity, anti-tumor efficacy and safety of HK054-V. The binding ability of IL12-Fc lead variants to activated PBMCs was analyzed by flow cytometry. The bioactivity of HK054-V was determined by assessing the activated T-cell proliferation and IFN-γ production in human PBMCs, and STAT-4 phosphorylation in a reporter gene assay. A murine surrogate, mHK054-V, was engineered to mimic HK054-V to evaluate the antitumor efficacy in MC38 and CT26 syngeneic tumor mouse models. Cytokine release assay was conducted by incubating HK054-V with peripheral blood mononuclear cells (PBMCs) from healthy donors. The safety profiles and pharmacokinetic (PK) behavior of HK054-V were characterized in non-tumor-bearing Balb/c mice. Results: HK054-V is a heterodimeric Fc-fused IL12, which was designed with reduced potency. HK054-V was observed to stimulate the proliferation of activated T cells and NK cells and induce production of IFN-γ in a dose-dependent manner. HK054-V could activate pSTAT4 signal in luciferase reporter gene assay and showed up to 100-fold reduction of potency compared to wild-type IL12-Fc. Human IL12 is inactive in mice, so in vivo anti-tumor activity was assessed by a murine surrogate, mHK054-V. mHK054-V demonstrated anti-tumor efficacy in syngeneic mouse models and was better tolerated than WT mIL12-Fc. Furthermore, mHK054-V has improved PK and therapeutic index in mice. Conclusion: These data demonstrate that HK054-V, a heterodimeric Fc-fused IL12 with reduced potency, retain strong anti-tumor efficacy with a favorable tolerability profile, which may provide a practical alternative to the systemic administration of IL12 for antitumor therapy. Citation Format: Yang Huang, Wenting Liu, Dayan Zhang, Pengfei Zhou, Weiming Zhou, Xiaoli Zeng, Qun Zhao, Liangwei Li, Guodong Shen, Liansheng Cheng. Heterodimeric Fc-fused IL12 shows potent antitumor activity and low toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6336.
Abstract 3088: Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1
Authors: James M. Smith, Bernard Barlaam, David Beattie, Iain Cumming, Graeme Robb, David Wilson, Davide Gianni, Bharath Srinivasan, Chris Stubbs, Judit Debreczeni, Mercedes Vazquez-Chantada, Elisabetta Chiarparin, James Lynch, Emma Dean
Journal: Cancer Research (2023)

Abstract Background: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. Despite this therapeutic potential, there is growing evidence that the first generation of clinical PRMT5 inhibitors may not be able to achieve high clinical efficacy due to PRMT5-driven (e.g. hematological) toxicities. Aims: In order to pharmacologically exploit the MTAP ‘collateral vulnerability’ mechanism for the potential of increased therapeutic index and clinical efficacy, next-generation PRMT5 inhibitors are required to bind PRMT5 in a cooperative manner with natural metabolite methylthioadenosine (MTA). Whilst MTAP-selective PRMT5 inhibitors have recently been reported,1,2,3 there is continued interest in identifying new and structurally diverse in vivo-quality compounds to further investigate this therapeutic opportunity. Results: To identify novel inhibitors of PRMT5 suitable for the MTAP line of sight, our hit finding strategy used a ‘biased’ biochemical high throughput screen of a 2.4M compounds collection. MTA-cooperative hits were validated using techniques including SPR and Xray crystallography. One series identified from this screen was extensively optimized using techniques including structure-based design to improve potency, MTAP selectivity and DMPK properties. Through these optimizations, we have identified AZ-PRMT5i-1, which shows potent in vitro cellular inhibition of PRMT5, over 50-fold MTAP selectivity margin, excellent selectivity against a broad panel of methyltransferases, and suitable oral PK properties. Conclusion: AZ-PRMT5i-1 is a structurally novel and potent PRMT5 inhibitor with high MTAP-selectivity suitable for use in in vitro and in vivo PRMT5-driven models of cancer’. Note: the structure of AZ-PRMT5i-1 will be disclosed at this meeting PRMT5 Cell SDMA: IC50 nM (HCT116 MTAP KO/WT) SDMA MTAP selectivity (fold) LogD/Rat heps CLint/Caco2 intr. A-B HTS hit A 660/4300 6.5 2.1/34/1.6 AZ-PRMT5i-1 5.4/290 54 2.8/5.0/48 References:1. J. Med. Chem. 65, 1749-1766 (2022); 2. WO2021163344; 3. WO2022026892 Citation Format: James M. Smith, Bernard Barlaam, David Beattie, Iain Cumming, Graeme Robb, David Wilson, Davide Gianni, Bharath Srinivasan, Chris Stubbs, Judit Debreczeni, Mercedes Vazquez-Chantada, Elisabetta Chiarparin, James Lynch, Emma Dean. Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3088.
Abstract 6636: Metformin suppresses tumor immune evasion through downregulation of PD-L1 expression in cancer cells and PD-1 expression in NK cells and T cells
Authors: Su Hwan Park, Jong-Ho Lee
Journal: Cancer Research (2023)

Abstract Up-regulation of programmed cell death 1 (PD-1) receptor on T cells and its ligand (PD-L1) on cancer cells is reported in various tumor microenvironment, and the interaction between PD-L1 and PD-1 inhibits the cytotoxic activity of NK cells and T cells, allowing cancer cells to evade immune destruction. Extensive studies suggested that metformin, the most widely used first-line drug for treatment of type 2 diabetes, had a potential efficacy of enhancing anti-tumor immune response. However, the detail mechanisms underlying the efficacy are unknown. Here, we showed that metformin decreases AKT-mediated β-catenin S552 phosphorylation and β-catenin transactivation in an AMPK activation-dependent manner, resulting in reduced CD274 transcription in cancer cells. In the cocultures of cancer cells with NK cells or T cells, cancer cells induced PD-1 protein stability and expression in the NK cells and T cells, these PD-1 upregulation was also observed in infiltrated NK cells and T cells in vivo mouse tumors. Metformin reduced the half-life and expression of PD-1 in an AMPK activation-dependent manner in vitro and in vivo. These inhibitory roles of metformin in PD-L1 expression in cancer cells and in cancer cell-induced PD-1 expression in NK cells and T cells led to ameliorated the cancer cell-reduced cytotoxic activity of NK cells and T cells and inhibited tumor growth in vivo models. These findings suggest that metformin may act as both PD-L1 and PD-1 blockades within tumor microenvironment, providing a mechanistic insight for the efficacy of metformin to improve immunotherapy in human cancer. Citation Format: Su Hwan Park, Jong-Ho Lee. Metformin suppresses tumor immune evasion through downregulation of PD-L1 expression in cancer cells and PD-1 expression in NK cells and T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6636.